Transdermal sampling strip and method for analyzing transdermally emitted gases

ABSTRACT

Transdermally emitted gasses are detected by applying a dermal sampling strip to the skin of a biological subject, capturing the gasses in a vapor space in the dermal sampling strip, and analyzing for at least one such gas captured in the vapor space of the dermal sampling strip. Analysis is preferably performed using an electrocatalytic cell, which can be mounted on the dermal sampling strip and form a wall of the vapor space.

CROSS REFERENCE TO RELATED APPLICATIONS

Not applicable.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

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INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC OR ASA TEXT FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM (EFS-WEB)

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STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINTINVENTOR

Not applicable.

BACKGROUND OF THE INVENTION Field of the Invention

Body fluids such as blood, urine and even breath are routinely analyzedfor medical, diagnostic and legal reasons. Among the many analytes thatare examined there are a number of small molecules like carbon dioxide(CO₂), oxygen (O₂), nitric oxide (NO), nitric dioxide (NO₂), hydrogenperoxide (H₂O₂), acetaldehyde (C₂H₄O), carbon monoxide (CO), ammonia(NH₃), hydrogen sulfide (H₂S), acetone (C₃H₆O), hydrogen cyanide (HCN),and formaldehyde (CH₂O) that have been associated with various diseasesor conditions. Breath analysis is interesting because it isnon-invasive, but in the case of trace gases such as H₂S and NH₃, theconcentrations of these compounds in exhaled air are too low to beanalyzed easily and inexpensively. This is further complicated by thepresence of bacteria in the respiratory system, moisture, and reactionsthat can occur.

Analysis for H₂S is of interest because the serum concentration of H₂Scorrelates with the risk of peripheral artery disease (PAD) and othercardiovascular disease. Excess H₂S is toxic and plasma concentrationsabove 20 μM cause mitochondrial poisoning and cell death. Therefore, away to quickly and accurately estimate serum H₂S levels can be animportant diagnostic tool.

Some molecules are emitted transdermally. In principle, the capture andanalysis of these transdermally emitted molecules has diagnostic orinvestigative value, and there have been attempts to develop devices,which accomplish this.

Description of Related Art

U.S. Pat. Nos. 4,274,418, 4,005,700, 4,836,907, 7,474,908, 8,048,677,8,527,023, and 7,862,698 describe devices comprising a body having agas-permeable boundary wall for placement on the skin of the subject, agas collection chamber in the body connected to an analysis instrument,a heating device to heat the skin area under the boundary wall and anelectronic control to control the heating device and monitor thetemperature of the skin area.

WO 2012/45047 describes an apparatus including a diffusion chamberadapted to receive an appendage of the patient; a measuring chamberpneumatically coupled to the diffusion chamber adapted to receive atleast a portion of one or more analytes from the diffusion chamber; atleast one optical sensor positioned in the measuring chamber, and atleast one optoelectronic component positioned outside of the measuringchamber for the remote detection of chemical interaction and/or physicalinteraction of the at least one optical chemical sensor.

U.S. Pat. No. 5,628,310 discloses an apparatus and method to enableminimally invasive transcutaneous measurements through fluorescencelifetime monitoring of an implanted element.

U.S. Pat. No. 8,386,027 discloses a device that contains (i) a handpiece, (ii) an abrasive tip, (iii) a feedback control mechanism, (iv)two or more electrodes, and (v) an electrical motor.

Other devices are described in U.S. Pat. Nos. 7,811,276, 8,393,199,7,266,404 and U.S. Patent No. 2007-0083094.

BRIEF SUMMARY OF THE INVENTION

The invention in one aspect is a method for measuring the transdermalemission of a gas through the skin of a biological subject, comprising

a) sealably mounting at least one dermal sampling strip on the skin ofthe subject, wherein the dermal sampling strip includes a samplecollection chamber that comprises (i) a skin contact side that is incontact with the skin when the dermal sampling strip is mounted and (ii)one or more walls, the skin contact side and the wall(s) togetherdefining a vapor space for collecting transdermally emitted gas, whereinthe skin contact side has one or more openings which create one or morefluid paths between the skin and the vapor space for collecting thetransdermally emitted gas;

b) collecting the transdermally emitted gas in the sample collectionchamber of the dermal sampling strip(s); and

c) analyzing for at the presence of at least one component of thetransdermally emitted gas collected in the sample collection chamber ofthe dermal sampling strip(s) by contacting the transdermally emitted gaswith a working electrode of an electrocatalytic cell, and measuring anelectrical signal created by a reaction of the at least one component ofthe transdermally emitted gas at the working electrode.

In another aspect the invention is a method for measuring thetransdermal emission of a gas through the skin of a biological subject,comprising

a) sealably mounting at least one dermal sampling strip on the skin ofthe subject, wherein the dermal sampling strip includes a samplecollection chamber that comprises (i) a skin contact side, (ii) one ormore walls, the skin contact side and the wall(s) together defining avapor space for collecting transdermally emitted gas, and wherein theskin contact side has one or more openings which create one or morefluid paths between the skin and the vapor space for collecting thetransdermally emitted gas, to form a seal between the skin and thesample collection chamber and such that the skin contact side of thedermal sampling strip is in contact with the skin

b) collecting the transdermally emitted gas in the sample collectionchamber of the dermal sampling strip(s); and

c) analyzing the transdermally emitted gas collected in the samplecollection chamber of the dermal sampling strip(s) for the presence ofat least one component selected from nitric oxide, nitric dioxide,hydrogen peroxide, acetaldehyde, carbon monoxide, ammonia, hydrogensulfide, acetone, hydrogen cyanide and formaldehyde.

In a third aspect, the invention is a transdermal gas analyzercomprising

a) a dermal sampling strip that includes a sample collection chamberthat includes (i) a skin contact side and (ii) one or more walls, theskin contact side and the wall(s) together defining a vapor space forcollecting transdermally emitted gas, and wherein the skin contact sidehas one or more openings which create one or more fluid paths betweenthe skin and the vapor space for collecting the transdermally emittedgas,

b) a detector for detecting the presence of one or more components ofthe transdermally emitted gas collected in the vapor space of the samplecollection chamber,

wherein the detector is in fluid communication with the vapor space suchthat a fluid path is defined from the skin to the detector such that thetransdermally emitted gas is transported through the fluid path from theskin to the detector without passing through a diffusion barrier.

In a fourth aspect, the invention is a dermal sampling strip comprisinga sample collection chamber, a detector and electrical contacts forconnecting the detector to a power source that provides electrical powerto the detector, wherein:

the sample collection chamber comprises (i) a skin contact side and (ii)one or more non-porous walls, the skin contact side and the non-porouswall(s) together defining a vapor space for collecting transdermallyemitted gas, and wherein the skin contact side has one or more openingswhich create one or more fluid paths between the skin and the vaporspace for collecting the transdermally emitted gas; and the detectorforms or is mounted onto at least one of the walls of the samplecollection chamber and is in fluidic communication with the vapor spaceof the sample collection chamber.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 is an exploded cross-sectional side view of an embodiment of atransdermal gas analyzer of the invention.

FIG. 2 is a cross-sectional side view of an embodiment of a transdermalgas analyzer of the invention, affixed to the skin of a living subject.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1, transdermal gas analyzer 1 includes dermal sampling strip 2,electronics module 3, optional removable protective film 8 and optionalprotective covering 34. Instead of or in addition to protective covering34, the entire device may be incorporated into a housing. Alternatively,dermal sampling strip 2 and electronics module 3 may be incorporatedinto separate housings, which may include means for removably andreplaceably attaching dermal sampling strip 2 to electronics module 3.

In the embodiment shown in FIG. 1, dermal sampling strip 2 includessample collection chamber 5. Sample collection chamber 5 includesperipheral walls 7 and working electrode 10, and skin side 6 whichtogether define vapor space 9. As shown, skin side 6 is open, forming afluid path between vapor space 9 and the skin of a subject to whichdermal sampling strip 2 is applied. In this embodiment, workingelectrode 10 forms a wall of sample collection chamber 5.

If desired, skin side 6 of sample collection chamber 5 may be coveredwith a screen, porous film or other layer (not shown) that definesmultiple openings that form fluid paths between vapor space 9 and theskin.

Similarly, vapor space 9 of sample collection chamber 5 may be partiallyor entirely filled with a porous material (such as a resilient polymerfoam that has at least 50% open and interconnected cells) and/or aparticulate solid, provided that such porous material and/or particulatesolid permits bulk gas transport from the skin through vapor space 9 andto detector 4. The presence of such porous material and/or particulatesolid provides a physical barrier between the skin of the biologicalsubject and the walls of sample collection chamber 5, and in particularany detector 4 which is mounted onto or forms a wall or walls of samplecollection chamber 5. If a porous material is present, it is mostpreferably a rigid or semi-rigid polymeric foam. The polymeric foam maybe a reticulated foam in which cell windows are absent. The fluid pathfrom the skin through vapor space 9 to detector 4 does not contain anyliquid, gel, membrane or other solid material which presents a diffusionbarrier (i.e., prevents bulk transport by requiring an emitted gas topermeate through a liquid, gel or semi-permeable membrane) to atransdermally emitted gas that enters vapor space 9.

In some embodiments vapor space 9 of sample collection chamber 5 maycontain a sorbent or other fixative for one or more transdermallyemitted gasses. This permits such gas or gasses captured in vapor space9 and to be analyzed using a separate detector, i.e., one that does notreside on dermal sampling strip 2 or transdermal gas analyzer 1, byremoving the sorbent and the gas captured on or in it. The use of asorbent or fixative also can prevent one or more components of thetransdermally emitted gas from reaching detector 4, while allowing oneor more other components of the gas to reach detector 4. This can beuseful, for example, to prevent interference and/or to isolate thesignal produced at detector 4 by one or more specific target gases.

By “sorbent” or “fixative”, it is meant some structure that binds atransdermally emitted gas to the sorbent or fixative. The bindingmechanism may be mechanical. For example, cells of a polymeric foam orother porous material can mechanically capture molecules of thetransdermally emitted gas. The binding mechanism also can be chemicaland/or physiochemical. A chemical sorbent or fixative engages in achemical reaction with a transdermal gas to bind the gas or somereaction product thereof to the sorbent or fixative. In the case of H₂S,for example, a chemical sorbent may include one or more materials thatare reactive with H₂S molecules, including, for example, metal ions(including alkali metal ions and/or salts thereof and transition metalcompounds such as hydrated iron (III) oxide), alcohol groups, isocyanategroups, epoxide groups, chlorine or chlorine precursor and the like. Aphysiochemical sorbent or fixative absorbs and/or adsorbs atransdermally emitted gas through a physisorption and/or chemisorptionmechanism. Examples of sorbent or fixative materials include variousforms of carbon, including carbon black, activated carbon, graphite,expanded graphite, carbon nanotubes and the like; molecular sieves,including zeolites; various high-surface area mineral powders, sorbentgels such as polymethylsiloxane polyhydrate, and the like.

In the embodiment shown, working electrode 10 of detector 4 isintegrated into sample collection chamber 5 and forms a wall thereof.This is an optional feature. Alternatively, for example, a separate wallstructure (not shown) may be interposed between detector 4 and vaporspace 9, such that vapor space 9 is defined by peripheral walls 7 andthe separate wall structure. In such a case, the separate wall structurepreferably includes one or more openings through which transdermallyemitted gas captured in vapor space 9 can pass through to detector 4.Any such separate wall structure should not form or include a diffusionbarrier.

The volume of vapor space 9 may be, for example, at least 10 mm³, atleast 100 mm³ or at least 250 mm³, up to 100 cm³, up to 25 cm³, up to 10cm³ or up to 1 cm³. The height (dimension transverse to the skin whenmounted) of vapor space 9 may be, for example, 0.5 mm to 2.54 cm, 0.1 to1 cm or 0.1 to 0.5 cm. The internal transverse dimensions of samplecollection chamber 5 (i.e., perpendicular to the thickness) each may be,for example, 0.5 to 25 cm or 2 to 15 cm, at their widest point. Thecross-sectional area of vapor space 9 (transverse to its height) may be,for example, 25 mm² to 625 cm², or 400 mm² to 250 cm². Vapor space 9 mayhave any convenient cross-sectional shape, such as a circle, ellipse,rectangle, square, other polygon, or other shape.

The materials of construction of peripheral walls 7 and any separatewall structure may be any non-porous material that is sufficientlyimpervious to gas to allow gases emitted from the skin of the biologicalsubject to be captured and held in vapor space 9 of sample collectionchamber 5. Suitable materials of construction may include one or more ofthe various organic polymers including Teflon, polycarbonate,polyethylene, polypropylene, polystyrene, polyimide,acrylonitrile-butadiene-styrene (ABS), high impact polystyrene (HIPS),nylon, fluoroelastomer and fluoro-rubber, various polyurethanes, etc.,as well as materials such as paper or other cellulosic materials andnon-reactive metals.

Sample collection chamber 5 may include various optional features. Onesuch optional feature is internal structure that creates a flow path oftransdermally emitted gas within vapor space 9 of sample collectionchamber 5. An example of such internal structure is, for example, aseries of raised ridges that produce one or more channels within vaporspace 9, thus defining a fluid flow path. Such a fluid flow path may beuseful, for example, in efficiently transporting transdermally emittedgases to detector 4, and/or for transporting transdermally emitted gasesout of sample collection chamber 5 for remote analysis.

Sample collection chamber 5 may include one or more gas inlet ports orheader, into which a gas can be introduced into vapor space 9, and/orone or more gas outlet ports or header, from which the sample or othergas can be withdrawn from vapor space 9. A gas inlet port and gas outletport each may be, for example, a solenoid valve or another type ofvalve, or a septum port, or the like. Such inlet and outlet ports areuseful for retrieving or recovering a captured transdermally emitted gasfrom vapor space 9 of sample collection chamber 5 for remote analysis.Such inlet and/or outlet ports can communicate with one or more channelsformed by internal structure within vapor space 9 of sample collectionchamber 5, such that a serpentine flow path is established from a gasinlet port to a gas outlet port. Arrangements such as these provide ameans for efficient recovery of captured emitted gases from vapor space9 and elimination of flow recirculation or dead zones within vapor space9. Upon opening a gas outlet port, captured emitted gasses can bewithdrawn from sample collection chamber 5 for remote analysis. A gasinlet port is generally opened during sample removal to facilitate flowof the captured gasses. A carrier or purge gas such as nitrogen or argoncan be introduced through a gas inlet port to push the trapped emittedgasses out of vapor space 9 of sample collection chamber 5.Alternatively, in certain circumstances, a vacuum can be drawn through agas outlet port to remove the captured transdermally emitted gasses andreplace the removed gasses with clean atmospheric gas.

In the embodiment shown in FIG. 1, detector 4 is an electrocatalyticcell 35 that, as shown, includes working electrode 10, counter electrode14, optional but preferred reference electrode 15 and electrolyte 13.Counter electrode 14, reference electrode 15 and electrolyte arecontained within housing 17. Working electrode 10, counter electrode 14and reference electrode 15 are in contact with electrolyte 13, but notin direct contact with each other. In the embodiment shown, electricallyconductive contact 11 extends through via sealed thru hole 16 of housing17, and connects to contact terminal 31 of electronics module 27.

Electrocatalytic cell 35 is designed and operated such that, when in thepresence of at least one target molecule, i.e., at least onetransdermally emitted gas, it creates a signal (typically an electricalor electromagnetic signal) that indicates qualitative and/orquantitative presence of such gas or gas molecules. The target moleculein some aspects is selected from one or more of carbon dioxide, oxygen,nitric oxide, nitric dioxide, hydrogen peroxide, acetaldehyde, carbonmonoxide, ammonia, hydrogen sulfide, acetone, hydrogen cyanide andformaldehyde. In the embodiment shown in FIG. 1, the capturedtransdermally emitted gas (including the target molecule) is broughtinto contact with working electrode 10, which is typically the anode ofelectrocatalytic cell 35. A voltage is applied to working electrode 10.Electrochemical reactions of the transdermal gas at the surface ofworking electrode 10 indicate the presence of the transdermal gasqualitatively and/or quantitatively.

Electrochemical methods for detecting H₂S are described, for example, byPandey et al., “A review of sensor-based methods for monitoring hydrogensulfide”, Trends in Analytical Chemistry 2012 32:87-99, Hodgson et al.,“Amperometric Gas Sensors with Detection Limits in the Low ppb Range”,Analytica Chemica Acta 1999, 393:43-48; and Yu et al., “ElectrochemicalH₂S Sensor with H₂SO₄ Pre-Treated Nafion Membrane as Solid PolymerElectrolyte,” Sensors and Actuator B 86 (2002) 259-265.

The working electrode of the electrocatalytic cell typically is at leastone metal surface at which an electrocatalytic reaction of a targetmolecule takes place. The working electrode may be created by coating orotherwise depositing a metal onto a polymeric base. The metal is onethat catalyzes a reaction that, depending on the particular targetanalyze molecule, may be an oxidation or reduction reaction, of thetarget molecule at the metalized electrode surface. Preferred metals aregold, silver, copper, lead and platinum, with gold being of particularinterest. The metal may be in a microcrystalline state. The metal mayalso adsorb the target analyte molecule from the gas captured in vaporspace 9.

The working electrode is also preferably permeable to water and hydrogenor other ions, particularly cations and protons that may be produced inthe reaction of the target molecule. In a preferred working electrode,the metal is coated or otherwise deposited onto a solid, semi-permeablemembrane. The membrane may be an organic polymer. An example of amembrane material is an ionomer film such as a sulfonated fluoropolymerfilm (or other cation-exchange membrane that has multiple anionic groups(such as strong or weak acid groups)). Such films are availablecommercially as Nafion® films. Other membrane materials of interestinclude anion-exchange membranes that have multiple cationic groups,including Selemion™ anion exchange membranes sold by Asahi Glass.

The working electrode and/or its polymeric membrane base may beroughened, deformed, or embossed to have microstructures such asmicropins, riblets, grooves, or corrugations to provide a higher exposedsurface area for better adhesion of the metal (electrocatalytic) surfaceand reaction with target analyte molecules. The plated metal preferablyhas a somewhat roughened surface as typically appears when the depositedmetal is in a microcrystalline state. The plated metal may have somediscontinuities, in the form of pores, cracks or the like which allowsmall molecules or ions to pass through the plated metal during thereaction of the target molecule, as needed to complete the reaction.

A suitable method for plating a polymer membrane with gold or othermetal is described, for example, in Jordan and Hauser, Anal. Chem. 69,558-562, 1997, and Cook, Journal of the Electrochemical Society, 235,187-189, 1990. In general, a film of the polymer is bathed in a solutionof a soluble metal compound, typically a halide or a sulfide, to absorbthe metal compound onto the film surface. The absorbed metal compound isreduced at the surface of the polymer film by contacting the polymerfilm with a reducing solution. In preferred cases in which the polymerfilm is semi-permeable, the film can be used to divide a cell into twosections, one of which contains the metal compound solution and one ofwhich contains the reducing agent solution. In this manner, the polymerfilm can be bathed in both solutions simultaneously, with the platingreaction occurring on or within the polymer film. Suitable metalcompounds are halides of the metal to be plated, such as silverchloride, copper chloride, gold chloride, lead chloride, gold hydrogenchloride (HAuCl₄) and the like. Suitable reducing agents includeborohydride salts such as sodium borohydride and sodium bisulfite. Thesesolutions can be stabilized by adjusting their pH into the basic rangesuch as by addition of caustic. A preferred deposition temperature is 5to 30° C., especially 10° C. and 20° C.

Working electrode 10 may be supported if necessary to minimize oreliminate flexing during operation. Flexing or other movement of theanode may lead to inaccuracies or variations in the current producedduring operation of the sensor. For example, working electrode 10 can besupported on its upper and/or lower surface, or may be sandwichedbetween two supporting plates. Any supporting plate on the side ofworking electrode 10 that faces vapor space 9 of sample collectionchamber 5 preferably is porous so that the target gas can permeate themand reach the electrode surface without blocking the reaction surface. Asupporting plate on the opposing side of working electrode is similarlyporous, to permit contact with electrolyte 13. Such supporting plate orplates tend to immobilize working electrode 10, reducing or preventingdeflections due to pressure fluctuations and mechanical shock, whichcould otherwise result in noisy and shifting sensor outputs.

Working electrode 10 is in contact with electrolyte 13. Electrolyte 13may be liquid, solid or a gel electrolyte. The electrolyte is capable oftransporting ions from working electrode 10 to counter electrode 14 (andreference electrode 15 if present) of electrocatalytic cell 35. Asuitable electrolyte is an aqueous solution that contains a mineral acidsuch as sulfuric or hydrochloric acid, such as a solution of 0.01 to 5 Msulfuric acid, perchloric acid, or hydrochloric acid, although solutionsof other mineral acids and even organic acids are suitable. Solid andgel electrolytes are also useful. Electrolyte 13 may be sealed within acase, housing or other system, which prevents leakage and isolates theelectrolyte from the outside environment. Such a cell housing mayinclude a venting means, by which gasses can enter and exit the cell tobalance pressures. The venting means should be substantially impermeableto the electrolyte so leakage does not occur. A suitable venting meansis a small window of a gas-permeable membrane in the housing of thecell. A suitable gas-permeable membrane is a polytetrafluoroethylenepolymer such as a Gore-Tex membrane, or similar type of hydrophobicmembrane. The cell housing can also function as the working electrode,counter electrode and/or reference electrode, if the case issufficiently electrically conductive.

In some embodiments, the working electrode and counter electrode (andpreferably the reference electrode as well) are coated or otherwisedeposited onto a porous membrane, provided that the electrodes areseparated from each other. The polymeric membrane has ionic groups. Thecounter and reference electrodes may be coated or otherwise depositedonto the side of such a porous membrane opposite of the workingelectrode. The polymeric membrane in such cases can form all or part ofthe electrolyte of the electrocatalytic cell, and/or hold some or all ofthe electrolyte within pores in the polymeric membrane. Such a designhas advantages in that the electrocatalytic cell can be made very thinand flexible. This facilitates incorporation into the dermal samplingstrip, particularly when the dermal sampling strip is designed to be forsingle- or limited-use and therefore disposable.

When the electrodes are arranged on a polymeric membrane as justdescribed, it may be beneficial to include an additional reservoir orelectrolyte fluid or gel, in fluid communication with the polymericmembrane, to prevent the polymeric membrane from drying out. This can bemounted on the dermal sampling strip itself, and/or otherwise onto thetransdermal gas analyzer of the invention.

Electrocatalytic cell 35 preferably also includes reference electrode 15against which the potential of working electrode 10 is measured.

Counter electrode 14 and reference electrode 15 can be made of anyconductive material, and may be made of the same metal as workingelectrode 10. Other materials used maybe graphite, stainless steel, orgold. Counter electrode 14 and reference electrode 15 are in electricalcontact with electrolyte 13 but not in electrical contact with eachother or with working electrode 10, except through electrolyte 13.Alternatively, the counter and reference electrodes maybe deposited,using for example a chemical vapor deposition approach, on the oppositeside of the working electrode polymeric base, whereby theelectrocatalyst (working electrode) is separated from the counterelectrode and reference electrode by the thickness of the membrane.

Alternatively, other detectors can be used in place of or in addition tothe electrocatalytic cell illustrated in FIG. 1, the detector being inthe most general sense any device or substance that analyzes for atleast one component of the transdermally emitted gas. Such component maybe selected from one or more of carbon dioxide, oxygen, nitric oxide,nitric dioxide, hydrogen peroxide, acetaldehyde, carbon monoxide,ammonia, hydrogen sulfide, acetone, hydrogen cyanide and formaldehyde.“Analyzes” and its cognates for purposes of this invention refer to anymethod for qualitatively (and preferably quantitatively) determining thepresence of the emitted gas. The particular method of analysis will ofcourse be selected in connection with the specific transdermally emittedgas(ses) being analyzed for. Examples of useful detectors for performingvarious analytical methods therefore include, for example, gaschromatographs, mass spectrometers, atomic absorption spectrometers,atomic emission spectrometers, atomic fluorescence spectrometers,various colorimeters (including devices that detect variations insurface reflectivity or absorptivity), infrared spectrometers, gelpermeation chromatographs, liquid chromatographs, raman spectrometers,x-ray fluorescence spectrometers, various chemical-based detectors andvarious electrochemical methods. The detector is selected to providequalitative and preferably quantitative analysis of the targettransdermally emitted gas(ses) in the concentration that accumulate inthe sample collection chamber during the sampling period. The detectorin some embodiments may be material that engages in a chemical reactionwith the transdermal gas, producing a sensible change (for example, inappearance, odor, etc.) that indicates the presence of the transdermalgas. In some cases, sorbent and/or fixative materials described abovemay exhibit such a sensible change upon contact with the transdermalgas, and will also function as a detector.

Multiple detectors may be included in the transdermal gas analyzer. Ifmultiple detectors are present, they may be of the same type, or may beof two or more different types.

The detector or a portion thereof may reside on dermal sampling strip 2itself, as shown in FIG. 1. In such embodiments, at least one detectorresides on dermal sampling strip 2, within or in fluid contact withvapor space 9 of sample collection chamber 5. As before, the detector orpart thereof may form or be mounted onto a wall of collection chamber 5that defines vapor space 9. In such embodiments, the capturedtransdermally emitted gas is brought into contact with the detector,which indicates the presence of the transdermally emitted gas (if simplyqualitative) and/or the quantity thereof (if also quantitative).

In the embodiment shown in FIG. 1, detector 4 and sample collectionchamber 5 collectively form dermal sampling strip 2. FIG. 1 illustratesa preferred embodiment in which dermal sampling strip 2 is removably andreplaceably attached to electronics module 3. In such embodiments, meansare provided to removably and replaceably attaching dermal samplingstrip 2 to electronics module 3. In FIG. 1, such means are hooks 23 ofelectronics module support 3, which “snap” over corresponding flanges 12of housing 17 and affix electronics module 3 to dermal sampling strip 2.Dermal sampling strip 2, flanges 12 and/or housing 17 are in suchembodiments made of a flexible material that reversibly deform slightlyunder pressure to permit flanges 12 to fit under hooks 23.

Other suitable means for removably and replaceably attaching dermalsampling strip 2 to electronics module 3 include, for example,mechanical fasteners such as clips, snapping closures, screw-typeclosures, post-and-slot mechanisms and other mechanical closures;magnetic fasteners, and various types of adhesives.

The dermal sampling strip of the invention (as well as the transdermalgas analyzer as a whole) preferably is non-invasive, i.e., lacks anyfeatures that penetrates and/or punctures the skin of the subject whenthe dermal sampling strip is applied and used in the manner describedherein.

In especially preferred embodiments, the dermal sampling strip of theinvention is flexible and bends to conform to the surface of the skin ofthe biological subject to form a seal between the skin and the samplecollection chamber.

In the embodiment shown in FIG. 1, electronic module 3 includeselectronic circuitry 27, which houses the electronic components oftransdermal gas analyzer 1, and optional module support 22.

Circuitry 27 includes the electronic components of transdermal gasanalyzer 1. Circuitry 27 is in electrical contact with detector 4. Insome embodiments, circuitry 27 includes circuitry for deliveringelectrical power from an electrical power source to detector 4, althoughthis may not be necessary in embodiments in which detector 4 is notpowered. Circuitry 27 may receive one or more electrical signals fromdetector 4, at least one of which is typically indicative of thequalitative and/or quantitative presence of one or more components of atransdermally emitted gas captured in vapor space 9 of sample collectionchamber 5. Thus, circuitry 27 may include circuitry for receiving andanalyzing an electrical signal produced by detector 4 in response to thepresence of at least one transdermally emitted gas, such as one or moregases selected from carbon dioxide, oxygen, nitric oxide, nitricdioxide, hydrogen peroxide, acetaldehyde, carbon monoxide, ammonia,hydrogen sulfide, acetone, hydrogen cyanide and formaldehyde.

In the specific embodiment shown in FIG. 1, electrical power is suppliedfrom circuitry 27 to electrocatalytic cell 35 via one or more ofelectrical contacts 31, 32 and 33, which are (when the device isassembled) in electrical contact with contact 11 of working electrode10, counter electrode 14 and reference electrode 15, respectively. Vias16, 19, 20, 21, 24, 25 and 26 extend through optional seal layer 18 andmodule support 22, permitting contact 11, counter electrode 14 andreference electrode 15 to make electrical contact with contact terminals31, 32 and 33 of circuitry 27.

In embodiments such as shown in FIG. 1, in which detector 4 is anelectrocatalytic cell, circuitry 27 preferably includes means forapplying a predetermined electrical voltage to working electrode 10, andmeans for measuring electrical conditions (typically current) producedwhen the target molecule reacts at working electrode 10. A simplegalvanometer or potentiostat is suitable for accomplishing both of thesefunctions. Preferred devices are capable of imposing a potential havingan amplitude (positive or negative) from 0.1 to 2.5, especially from 0.5to 1.5 volts, to the working electrode, relative to a standard hydrogenelectrode (SHE), and of measuring current amplitudes in the range offrom 1 nA to 100 mA, especially from 0.1 μA to 1 mA. The circuitry maybe, for example, an analog circuit that uses a pair of op amps, one as abiased emitter follower to provide the desired potential to the cell,and the other as a signal amplifier to measure the current produced bythe cell. The circuitry may include one or more digital controllers,which facilitates real-time control of the applied voltage, baselineoffsets and signal amplifier gain.

A number of commercially available galvanometers and potentiostats areuseful. An example of a potentiostat with equally suitable performanceis a Model 273-A potentiostat/galvanostat from Princeton AppliedResearch, Oak Ridge, Tenn., operated with CorrWare software (fromScribner Associates, Southern Pines, N.C.). Another suitable example ofa potentiostat is a Custom Sensor Solutions model 1401.

Circuitry 27 may include at least one human-readable display which, inresponse to the electrical conditions created by the oxidation orreduction of a target chemical at the working electrode, indicates thepresence or absence of the target chemical in measurable quantities inthe sample gas and/or the concentration of such target chemical in thesample gas. The display can be a visual type, a sonic type or some othersuitable type. Combinations of various types can be used. A simple typeof display is a light, such as an LED, which can be turned off or on (ordisplay different colors) in response to the current produced when thetarget chemical is detected by detector 4, to indicate the presence orabsence of the target molecule. For example, such a light can be set tobe “off” until a target molecule is detected, in which case it becomesactivated. A more complex display can be an LCD display or othergraphical user interface, which can be designed to indicate thequalitative presence or absence of the target molecule, or which canprovide quantitative information as to the concentration of targetmolecule in the sample gas stream.

Circuitry 27 also preferably includes an electrical power source and/ormeans for connection to an electrical power source, such as a cord,wiring and/or plug, or a port for receiving such a cord, wiring or plug.A suitable electrical power source is a direct current source such asbattery 29, but an AC source in combination with a transformer (toproduce DC power) can also be used.

Circuitry 27 may further include one or more communication modules 30that are operable to communicate information (including data obtainedfrom detector 4) to a remote device for, e.g., analysis and/or displayand/or to receive communications from a remote device. Such acommunication module may include one or more wireless communicationsdevices that transmit an electromagnetic signal according to, forexample the Bluetooth protocol, the IEEE 802.11 protocol (Wi-Fi), or viaa cellular telephone protocol. Alternatively or in addition, acommunication module may be adapted to deliver and/or receive acommunication signal over a wire or cable, such as by delivering thesignal to a communication port such as a USB port, HDMI port, opticalcable port or other port 28 mounted onto circuitry 27.

Circuitry 27 may further include one or more user interfaces and/orcontrols, which may be graphical and/or mechanical, to permit a user tooperate transdermal gas analyzer 1, and/or monitor or control itsoperation.

Circuitry 27 may also include various auxiliary electronic and/orelectrical components, including but not limited to one or moremicroprocessors for operating the various other electronic components orthe device as a whole.

Although shown in FIG. 1 as a single device, circuitry 27 may consist oftwo or more discrete modules, each of which contains one or more of thecomponents described above.

Other optional features shown in FIG. 1 include protective covering 34,which may be transparent, rim 37 and removable protective film 8, whichseals the opening(s) on skin side 6 of sample collection chamber 5 untilthe device is ready for use, at which time protective film 8 is removedso the opening(s) in skin side 6 of sample collection chamber 5 are opento the skin of the subject.

In its broadest scope, the target molecule can be any one or moretransdermally emitted gas. By “gas” it is meant any molecule that at thesubject's ordinary body temperature (36.5-37.5° C. for humans) escapesfrom the surface of the subject's uncovered skin in the form of a vapor.Note that the boiling temperature of the material may be higher than thebody temperature of the subject. The gas may have a vapor pressure of atleast 75 mm Hg or at least 100 mm Hg at 38° C. The method of theinvention is particularly suitable for the capture and analysis of smallmolecules, especially those having molecular weights of up to about 100g/mol. The target molecule can be one or more of carbon dioxide, oxygen,nitric oxide, nitric dioxide, hydrogen peroxide, acetaldehyde, carbonmonoxide, ammonia, hydrogen sulfide, acetone, hydrogen cyanide andformaldehyde.

The target molecule is detected by sealably mounting at least one dermalsampling strip of the invention onto the skin of a biological subject,and collecting the transdermally emitted gas in the sample collectionchamber of the dermal sampling strip(s), and analyzing for one or moretarget molecules. The biological subject may be a living animal,particularly a living mammal and especially a domesticated mammal orhuman. The biological subject may also be plant tissue, particularly afruit, leaf, or vegetable such as apples, pears, peaches, any type ofcitrus fruit, bananas and other tropical fruit, melons, squash,tomatoes, peppers and the like. The “skin” of the subject is forpurposes of this invention the outermost tissue layer, i.e., theepidermis of an animal and the peel, husk or shell of a fruit orvegetable.

Sealably mounting the dermal sampling strip can be accomplished invarious ways. Because the skin and underlying musculature is usuallysomewhat soft and flexible, an adequate seal often can be obtainedsimply by applying sufficient pressure onto dermal sampling strip 2.Such applied pressure, such as can be applied by the subject itself oranother person (who could be, for example a clinical technician). Undersufficient pressure, the skin will deform slightly and conform to thesurface of skin side 6 of dermal sampling strip 2 to create a seal.Therefore, a separate sealing means may not be necessary.

Alternatively, dermal sampling strip can be secured to skin by separatemeans, such as, for example, a tape, gauze, sleeve, clamp, band or wrapthat is applied over the dermal sampling strip and which adheres to orotherwise secures the strip to the skin such that a seal forms betweenthe skin and the skin side of the sample collection chamber. Varioussurgical tapes are suitable for this purpose.

Alternatively, the sealing and mounting means can be incorporated intothe dermal sampling strip 2 itself and/or transdermal gas analyzer 1. Inthe embodiment shown in FIG. 1, such sealing and mounting means includesrim 37, which is affixed to skin side 6 of peripheral walls 7 of samplecollection chamber 5 of dermal sampling strip 2. In such embodiment,dermal sampling strip is sealingly mounted to the skin of the subjectvia direct contact between the skin 40 and rim 37, as shown in FIG. 2.By “sealingly mounted” it is meant that the dermal sampling strip ismounted to the skin of the biological subject such that gasses emittedfrom the skin of the subject in the area covered by the dermal samplingstrip 2 are prevented from escaping the interface between the skin andthe dermal sampling strip, so those gasses become captured in the vaporspace of the sample collection chamber.

Rim 37 may be replaced or supplemented with alternative means forsecuring dermal sampling strip 2 to skin 40. One or more sleeves,clamps, bands and/or wraps that are permanently affixed to transdermalgas analyzer 1 and/or dermal sampling strip 2 may perform the necessarysealing and mounting function.

FIG. 2 illustrates an embodiment of the mounting of transdermal gasanalyzer 1 of the invention onto the skin 40 of a living animal subject.Transdermal gas analyzer 1 includes dermal sampling strip 2 andelectronics module 3. Dermal sampling strip 2 includes sample collectionchamber 5 and detector 4. Skin contact side 6 in this embodimentincludes porous plate 49 and sliding closure 48, which together definean optional feature, i.e., a recloseable skin-side opening. Porous plate49 includes multiple openings 46A and sliding enclosure 48 includesmultiple openings 46.

Sliding closure 48 is slidably mounted onto dermal sampling strip 2along skin contact side 6. When in an open position (as shown), openings46 align with openings 46A to create a flow path for the transmission ofgasses from skin 40 into vapor space 9 of sample collection chamber 5.When moved into a closed position, openings 46 and openings 46A are nolonger aligned, closing the flow paths from skin 40 into vapor space 9.Vapor space 9 of sample collection chamber 5 is thus sealed, trappinggasses emitted from skin 40 inside sample collection chamber 5. In analternate design, sliding closure 48 lacks pores or other openingsthrough which emitted gasses can pass. In such an alternate design,sliding closure 48 slides out of dermal sampling strip 2 to openopenings 46A of porous plate 49 and create a flow path for gasses fromskin 40 into vapor space 9, and can then be replaced to seal samplecollection chamber 5.

Alternate recloseable openings for skin side 6 of dermal sampling strip2 include, for example, a movable plate mounted on skin contact side 6such that dermal sampling strip 2 is compressed, the moveable platemoves inward, forming openings 4 around some or all of the periphery ofskin contact side 6 of sample collection chamber 5. Means such assprings or a flexible but resilient foam material that occupy some orall of sample collection chamber 5 are provided to return such amoveable plate to its original position when dermal sampling strip 2 isnot under compression. Such a resilient foam material preferably is anopen-celled (at least 50% open and interconnected cells, more preferablyat least 80% open cells) foam, as to not form a diffusion barrier fortransdermally emitted gases.

In the embodiment shown in FIG. 2, the means for securing dermalsampling strip 2 to skin 40 is adhesive rim 37. Adhesive rim 37 ismounted on skin contact side 6 of dermal sampling strip 2, and providesa seal between skin 40 and dermal sampling strip 2. Such seal preventsgasses emitted from skin 40 in the area covered by dermal sampling strip2 from escaping the interface between skin 40 and dermal sampling strip2, so that such emitted gasses pass through openings 46 and 46A intovapor space 9 of sample collection chamber 5, where they are captured.Adhesive rim 37 thus performs two functions in the embodiment shown inFIG. 2; i.e., sealing and adhesion.

As shown in FIG. 2, skin 40 includes stratum corneum 40A and viableepidermis 40B, which are supplied with blood through artery 41.Capillaries 43 transfer blood from artery 41 through viable epidermis40B and to vein 50. Blood gasses (indicated as H₂S) are emitted from theblood as it traverses viable epidermis 40B and move in the generaldirection indicated by arrow 45, through stratum corneum 40A, openings46 and 46A and into sample collection chamber 5, where they arecaptured.

In operation, dermal sampling strip 2 is applied to skin 40 and held inplace via adhesive rim 37, which seals the periphery of dermal samplingstrip 2 to skin 40 and prevents the escape of gasses from the interfacebetween dermal sampling strip 2 and skin 40.

Rim 37 is optional but preferred. Rim 37 suitably is made at least in apart of an elastomeric material, preferably an elastomeric foam materialsuch as a polyurethane, silicone or other rubbery material. Rim 37preferably is compressible. When dermal sampling strip 2 is applied tothe skin of the biological subject, rim 37 forms a seal between the skinand the sample collection chamber. Rim 37 may consist of or include anadhesive layer that bonds to the skin of the biological subject.

Once in place, sliding closure 48 is opened, aligning openings 46 and46A and creating a flow path for gasses emitted through skin 40 intovapor space 9 of sample collection chamber 5. After gasses are collectedfor a period of time (the “sampling time”), sliding closure 48 isclosed, sealing sample collection chamber 5. The sampling time may bemeasured and/or predetermined so transdermal emission rate data can becalculated.

The detection of one or more transdermally emitted gases collected insample collection chamber 5 is performed by detector 4.

In preferred embodiments as shown in FIGS. 1 and 2, analysis for thetarget transdermally emitted gas is performed via a detector such asdetector 4 that is mounted (permanently or removably and replaceably)onto dermal sampling strip 2. Alternatively, the captured emitted gas istransferred from the dermal sampling strip to a separate apparatus forremote analysis. This can be performed, for example, by transporting thecontents of the sample collection chamber from the dermal sampling stripto a separate analytical device or into a collection vessel that is thentaken for analysis. The captured gas itself can be transported in thismanner. If the transdermal gas is captured on a sorbent or fixative asdescribed above, the sorbent or fixative with the captured transdermalgas may be removed from the dermal sampling strip and taken for remoteanalysis. Alternatively, the entire dermal sampling strip can be takento remote analysis.

Detection of the captured transdermally emitted gasses can be performedcontinuously, if the detector resides on or is mounted onto the dermalsampling strip (as shown in FIGS. 1 and 2) or the vapor space of thesample collection chamber is continuously in communication with a remotedetector. More typically, however, (due to the low rates of emission ofgasses through the skin) the transdermally emitted gasses are capturedand permitted to concentrate in the sample collection chamber, and thentaken once or periodically for analysis. Preferably, the dermal samplingstrip is affixed to the skin and left in place for a predeterminedand/or measured period of time. Preferably, a quantitative measurementof at least one target molecule is made. The duration of samplecollection and the measured quantity of transdermally emitted gasespermits a calculation of an estimated emission rate through the skin.The rate of gas emission can be used to estimate the concentration ofthe emitted gas in the blood.

For a gas such as H₂S, for example, one way of performing this estimateis through the relationship:

$\begin{matrix}{{\frac{d}{dt}\left( n_{H_{2}S} \right)} = {\left( \frac{A_{s}}{\delta/D} \right) \cdot {\left\lbrack {\chi_{i} - {\left( \frac{R \cdot T \cdot k_{H}}{\forall_{s}} \right)n_{H_{2}S}}} \right\rbrack.}}} & (1)\end{matrix}$wherein t is sampling time (s), n_(H) ₂ _(Ss) is moles of H₂S gas in thestrip, χ_(i) is molar concentration of free H₂S in blood, D isdiffusivity of H₂S through skin (reported to be approximately 6×10⁻⁷cm²/s), δ is skin thickness (cm), ∀_(s) is void volume in the strip(mL), A_(s) is dermal surface area covered by the strip (cm²), R is theUniversal Gas Constant (8.314 N·m/mol-K), T is gas temperature (K), andk_(H) is the Henry's law constant for solubility of H₂S in skin(mol/L-bar). One can solve Equation (1) for finding n_(H) ₂ _(S) (orC_(H) ₂ _(S)=n_(H) ₂ _(S)/n_(air), gas concentration in ppm). Equation 1can be generalized to estimate blood concentrations of othertransdermally emitted gases by substituting constants applicable to thespecific transdermally emitted gas.

At the t→0 asymptotic limit, the rate of gas emission through the skinis linear and is independent of the solubility of the gas in the skin.Therefore, at times close to t=0, the rate of change of theconcentration of the captured gas in the sample collection chamber isindicative of χ_(i), the molar concentration of the free gas in theblood. Measuring the captured gas at one or more times close to t=0therefore provides an estimate of χ_(i). To estimate χ_(i) in thismanner, the sampling time may be, for example, up to 1 hour, up to 5minutes or up to 2 minutes.

The concentration of a transdermally emitted gas in the samplecollection chamber will increase over time, as long as the strip isapplied to the skin and the sample collection chamber is open to theskin surface, until the concentration reaches equilibrium, or a limitingconcentration of the transdermally emitted gas. This limitingconcentration is indicative of the solubility of the gas in the skin.Therefore, in alternative embodiments, the sampling time is long enoughthat the concentration of the gas approaches or reaches the limitingconcentration. The sampling time in this case may be, for example, atleast 2 minutes, or at least 5 minutes. A preferred time is 15 minutesto 24 hours, depending on the particular gas and physiologicalconditions.

By applying a dermal sampling strip and measuring both the rate ofemission of the transdermally emitted gas and the value at close toequilibrium, one can therefore obtain estimates of both the molarconcentration of the gas in the blood and the solubility of the gas inthe skin. Each of these parameters may be indicative or diagnostic of aparticular medical condition or disease (or lack thereof), or othercondition such as the presence or absence of a substance (such as ametabolize) in the subject.

In some embodiments, multiple dermal sampling strips of the inventionare affixed to a subject's skin as described before and correspondinglymultiple samples of transdermally emitted gas are collectedsimultaneously and/or serially and analyzed. For example 2 to 20, 2 to10 or 2 to 5 dermal sampling strips may be used in such manner.

The use of multiple dermal sampling strips in this way has severalpotential advantages. In some instances, the captured transdermallyemitted gases from multiple strips can be combined for analysis. Thispermits, for example, larger quantities of the transdermally emitted gasto be captured, leading to easier and often more accurate analysis. Thisis an important advantage, because of the very low concentrations of thetransdermally emitted gases that typically are captured.

Another advantage of using multiple dermal sampling strips in this wayis that the time needed for sample collection can be reduced.

The transdermally emitted gases captured in each individual dermalsampling strip can of course be analyzed for separately from thosecaptured in the other dermal sampling strips, if desired. By doing so,one can obtain comparative rates of emission of one or moretransdermally emitted gases from different parts of a subject's body.Differences in the rates of emission between different parts of thesubject's body may in some instances be indicative or even diagnostic ofdisease and/or abnormal function, for example, blood circulationabnormality. In the case of H₂S emissions, for example, a significantdifference in rate between the limbs of a living animal (including ahuman subject) is often indicative of peripheral artery disease in oneor more of the limbs. By applying dermal sampling strips to, forexample, both legs and/or both arms of a subject, or to a limb and tothe torso, collecting the transdermally emitted gases and analyzing forH₂S emitted from each limb separately, or from the limb and torsoseparately, and comparing the results, one therefore can obtain anindication (or lack thereof) of peripheral artery disease. Moregenerally, by applying multiple dermal strips symmetrically to parts ofa subject's body, one can differentially detect and measure thetransdermal emission of one or more gasses from, for example, opposinglimbs or other symmetrical body parts. Differences in emission ratesbetween such symmetrical body parts may be indicative of a medicalcondition or disease.

In 1-methylcyclopropene-treated or untreated fruits and vegetables, theemission of metabolites such as ethylene, acetaldehyde, and ethanol isindicative of ripeness and/or decay. Measuring the emission of suchmetabolites in accordance with this invention therefore can provide anindication of whether the fruit or vegetable is becoming ripe, and alsocan provide an indication of the state and/or rate of ripening. Further,fruits, vegetables, and flowers are often treated with1-methylcyclopropene (1-MCP), a synthetic molecule known as ethyleneblocker, to prevent ripening. Monitoring 1-MCP on these products wouldfacilitate determination of whether or not they can be classified asorganic.

Alternatively, or in addition, the gasses captured by different samplingstrips can be analyzed for different analytes (“orthogonal detection”).Orthogonal detection can be used to isolate specific abnormalities ormedical conditions, or to screen for or diagnose two or more medicalconditions or diseases at the same time.

The preferred method of analysis is via the electrocatalytic reaction atthe working electrode of an electrochemical cell, which preferably ismounted onto the dermal sampling strip as shown in FIG. 1.

The electrocatalytic approach offers several important advantages.Electrocatalytic methods can reliably detect quantities of many targetgases, particularly H₂S, at concentrations as low as 1 part per billionby volume in the sample collection chamber. Accordingly, samplecollection times can be quite short (as little time is usually needed toachieve such concentrations of the target gas in the sample collectionchamber), and reliable emission rate estimates can be made quickly andeasily. The electrocatalytic detector can, through selection ofparticular working electrode and applied potential, be set to detectspecific gasses, which often react selectively in the presence ofparticular working electrode metals and particular applied potentials.If two or more transdermally emitted gases react simultaneously undercertain conditions, one can often achieve quantitative estimates of theamounts of each gas, by sequentially operating the cell at differentpotentials, at one of which only one of the transdermally emitted gasreacts. By sequentially operating the cell at different potentials, itis also possible in some cases to determine the presence and/or amountsof two or more transdermally emitted gasses from a single collectedsample.

Another important advantage of the invention, particularly whenelectrocatalytic detection methods are used, is that it usually is notnecessary to heat the skin to accelerate the transmission of gasses outof the skin and into the sample collection chamber. The ability todetect, qualitatively and/or quantitatively, very small concentrationsof many transdermally emitted gases, makes it unnecessary to heat theskin or otherwise accelerate the emission rate. Therefore, samplecollection preferably is performed at the body temperature of thesubject (if a living animal), or at ambient temperature (in the case offruits, vegetables and non-living subjects), without applied heating orcooling.

Still another advantage of the invention, particularly whenelectrocatalytic detection methods are used, is that response times tendto be on the order of seconds or even fractions of a second.

One method of detecting H₂S involves a dual detection, one of H₂Sdirectly and one of SO₂ obtained by catalytic oxidation of the H₂S. Insuch a method, the captured transdermal gasses are removed from thesample collection chamber and split into two samples. Alternatively, twodifferent samples are captured using two different dermal samplingstrips. One of the samples is passed through an analytical deviceadapted to detect H₂S, such as an electrocatalytic sensor in which theworking electrode (which may be a gold electrode) is set at a biaspotential of approximately 200 mV vs. MSE. The second stream passesthrough a catalytic oxidation unit to convert the H₂S molecules to SO₂.The oxidation catalyst may be, for example, a molecular sieve or γ-Al₂O₃particles. The gases exiting the catalytic oxidation unit are air cooledif necessary and then analyzed for SO₂. An alternative method ofcreating a SO₂ stream is to pass the sample gas containing the targetH₂S molecules through a raw (none surface-treated or heat-treated)activated carbon fiber (ACF) matrix, which adsorbs the H₂S gas andconcentrates it as described by Feng et al., “Adsorption of HydrogenSulfide onto Activated Carbon Fibers: Effect of Pore Structure andSurface Chemistry,” Environ. Sci. Technol. 2005, 39, 9744-9749. Onceconcentrated, some or all of the H₂S can be thermally converted to SO₂.The gases are released from the ACF matrix through a temperatureprogrammed desorption (TPD) process, releasing the different gas speciesat various temperatures. This process most likely creates a strong SO₂peak at a temperature of 300° C. to 400° C. The SO₂ detector may beanother electrocatalytic cell maintained at a bias potential ofapproximately −65 mV vs. MSE and optimized for reaction and sensing ofSO₂ molecules.

Alternatively, the use of a heat-treated ACF (oxidation at 200° C. andheat treatment in nitrogen at 900° C.) will result in adsorption of H₂Sgas during the adsorption cycle, a part of which is converted to SO₂,and both SO₂ (250° C. to 300° C.) and H₂S (300° C. to 350° C.) moleculesare released during the TPD process. This approach would only requireone detector, since both peaks are discriminated by TPD. The dualdetection gives independent measurements of the H₂S in sample collectionchamber.

Example

A transdermal gas analyzer as generally shown in FIG. 1 is evaluated inthe detection of hydrogen sulfide. The working electrode is a gold layerdeposited onto a Nafion polymer membrane. The electrolyte is a dilutesulfuric acid solution. The reference and counter electrodes aregraphite. The circuitry maintains a voltage of approximately 200 mV vs.MSE across the electrocatalytic cell, and includes a potentiostat thatmeasures current produced at the working electrode due to the catalyticreaction of hydrogen sulfide.

In a first test, a standard gas containing 1 part per million H₂S isinjected into vapor space 9, followed by a steady injection of a purgegas (air). The detector produces a current of about 0.017 mA in responseto the injected gas. The signal decays rapidly as the test sample isreplaced by the purge gas.

In a second test, test gases containing 10, 50 and 100 parts per billion(ppb) H₂S are injected into vapor space 9, to simulate gasconcentrations expected to be seen from a living mammal subject in areasonably short sample time. The sensor responds by producing currentsof about 0.06, 0.22 and 0.38 microamps. These results indicate astraight-line correlation of produced current to H₂S concentration.

What is claimed is:
 1. A method for measuring the transdermal emissionof H₂S gas through the skin of a human, comprising a) sealably mountingat least one dermal sampling strip on the skin of the subject, whereinthe dermal sampling strip includes a sample collection chamber thatcomprises (i) a skin contact side that is in contact with the skin whenthe dermal sampling strip is mounted, (ii) one or more walls, the skincontact side and the wall(s) together defining a vapor space forcollecting transdermally emitted gas, wherein the skin contact side hasone or more openings which create one or more fluid paths between theskin and the vapor space for collecting the transdermally emitted gas,(iii) raised ridges defining one or more channels within the samplecollection chamber, (iv) a gas inlet port in communication with the oneor more channels within the sample collection chamber and (v) a gasoutlet port in communication with the one or more channels within thesample collection chamber; b) collecting the transdermally emitted gasin the sample collection chamber of the dermal sampling strip(s); c)withdrawing the transdermally emitted gas from the sample collectionchamber by introducing a carrier or purge gas through the gas inlet portto push the trapped emitted gasses out of the vapor space of the samplecollection chamber or drawing a vacuum through the gas outlet port toremove the captured transdermally emitted gasses; d) analyzing thewithdrawn transdermally emitted gas for the presence of H₂S bycontacting the transdermally emitted gas with a working electrode of anelectrocatalytic cell, and measuring an electrical signal created by areaction of the H₂S gas at the working electrode; and e) calculating anestimated emission rate of H₂S through the skin and estimating theconcentration of the H₂S in the blood of the biological subject from theestimated rate of H₂S emission through the skin.
 2. A method formeasuring the transdermal emission of H₂S gas through the skin of ahuman, comprising a) sealably mounting at least one dermal samplingstrip on the skin of the subject, wherein the dermal sampling stripincludes a sample collection chamber that comprises (i) a skin contactside that is in contact with the skin when the dermal sampling strip ismounted, (ii) one or more walls, the skin contact side and the wall(s)together defining a vapor space for collecting transdermally emittedgas, wherein the skin contact side has one or more openings which createone or more fluid paths between the skin and the vapor space forcollecting the transdermally emitted gas, (iii) raised ridges definingone or more channels within the sample collection chamber, (iv) a gasinlet port in communication with the one or more channels within thesample collection chamber and (v) a gas outlet port in communicationwith the one or more channels within the sample collection chamber; b)collecting the transdermally emitted gas in the sample collectionchamber of the dermal sampling strip(s); c) withdrawing thetransdermally emitted gas from the sample collection chamber byintroducing a carrier or purge gas through the gas inlet port to pushthe trapped emitted gasses out of the vapor space of the samplecollection chamber or drawing a vacuum through the gas outlet port toremove the captured transdermally emitted gasses; d) analyzing thewithdrawn transdermally emitted gas for the presence of H₂S bycontacting the transdermally emitted gas with a working electrode of anelectrocatalytic cell, and measuring an electrical signal created by areaction of the H₂S gas at the working electrode; and e) estimating aserum concentration of the H₂S gas.
 3. The method of claim 2 wherein instep b) the dermal sampling strip is affixed to the skin and left inplace for a predetermined and/or measured period of time during whichtransdermally emitted gasses are captured and permitted to concentratein the sample collection chamber and in step c) a quantitativemeasurement of H₂S in the captured and concentrated transdermallyemitted gas is made.
 4. The method of claim 2, wherein in step d) thereaction of the H₂S gas at the working electrode creates an electricalsignal that indicates the qualitative and/or quantitative presence ofsaid H₂S gas in the vapor space of the sample collection chamber and thedermal sampling strip further includes or is in electrical connectionwith means for detecting and/or measuring said current.
 5. The method ofclaim 2, wherein the working electrode includes a metal deposited ontoat least one surface of a polymeric membrane.
 6. The method of claim 2,wherein in step a) multiple dermal sampling strips are sealably mountedon the skin of the subject and in step b) transdermally emitted gasesare captured in the sample collection chambers of the multiple dermalsampling strips.
 7. The method of claim 6, wherein in step d) thetransdermally emitted gases captured in the multiple dermal samplingstrips are each is separately analyzed for the presence of the H₂S gas.8. The method of claim 7, wherein in step a) the multiple dermalsampling strips are sealably mounted onto the skin in different areas ofthe subject's body, the method further comprising obtaining differentialrates of emission of said H₂S gas through the skin in the differentareas of the subject's body.
 9. The method of claim 8, wherein in stepa) dermal sampling strips are sealably mounted to skin on opposing limbsof the subject's body, the method further comprising obtainingdifferential rates of emission of said transdermally emitted H₂S gasthrough the skin of each of the opposing limbs.
 10. The method of claim8, wherein in step b) a dermal sampling strips is sealably mounted tothe skin of the subject's torso and a dermal sampling strip is sealablymounted to at least one limb of the subject's body, the method furthercomprising obtaining differential rates of emission of saidtransdermally emitted H₂S gas through the skin of the torso and the skinof at the least one limb.
 11. The method of claim 2, wherein the skin ofthe biological subject is not heated during step b).
 12. The method ofclaim 2 wherein the dermal sampling strip does not penetrate the skin ofthe biological subject.
 13. The method of claim 2, wherein the dermalsampling strip is flexible and bends to conform to the surface of theskin of the biological subject to form a seal between the skin and thesample collection chamber.
 14. The method of claim 2 wherein the dermalsampling strip includes an elastomeric peripheral rim which iscompressed when the dermal sampling strip is applied to the skin of thebiological subject to form a seal between the skin and the samplecollection chamber.